July 20, 2018
5 min read

Trigeminal dysphoria: The ophthalmic highway to hell

A specialist considers neurogenic eye pain, relevant anatomy and neural stimulation.

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Anyone who takes care of patients with dry eye disease has had this experience. A patient comes into the office complaining of severe, life-altering eye pain, and for the life of you there is nothing you can find on his or her exam that explains their pain. They arrive on several DED medications and have a history of undergoing “save the day” treatments such as LipiFlow or intense pulsed light. You look at their eyes, see the sorrow in their faces, and all you want to do is hug every other eye doctor who took care of them because what you see is nothing short of brilliant DED care.

You are now the doctor of a patient with neurogenic eye pain.

As a doctor who spends roughly one-third of my clinic time taking care of DED patients, this is by far the most confusing and challenging scenario. We have all become familiar and comfortable with the two main types of DED, aqueous deficient and evaporative. Recently it has been proposed that there is a third type of DED called neurogenic dry eye. Frankly, I have been struggling with this. I have always understood that the pain is real and that in some cases it can be traced back to DED as an inciting cause. How this translates into a third type of DED has eluded me. I believe that this type of eye pain is not a true, distinct and different form of DED but is rather a specific type of trigeminal dysphoria that should be grouped with migraine, trigeminal neuralgia and the like.

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Every good discussion, and especially every good technical discussion, begins with an investigation of vocabulary. Medical discussions should also begin with an understanding of the relevant anatomy. Once again, the anatomy you need to know goes back to first semester, first year of med school and the cranial nerves. Your vocabulary lesson is a deep dive into the vagaries of nerve conduction. The pain is a form of allodynia, a central pain-processing abnormality, not an active disease on the ocular surface.

Man, if you thought the innervation of the lacrimal functional unit (Steve Pflugfelder) was challenging, the seemingly infinite number of places that the trigeminal nerve actually touches will blow you away. In her Hoyt Lecture at the 2017 American Academy of Ophthalmology meeting, the neuro-ophthalmology equivalent of our Binkhorst Lecture, Kathleen Digre from Moran Eye Center provided the best explanation of aberrant trigeminal eye pain I have come across (hat tip to Dick Lindstrom and Andy Corley of eyeBrain Medical). As your faithful scribe, I will do my best to tease out the DED highlights, but you would do well to read the original article in the Journal of Neuropathology & Experimental Neurology not only for the DED angle but also to better understand the link between the eye and migraine.


Let us take a brief tour of the trigeminal nerve (trigger alert: hard-core anatomy coming). Unlike most cranial nerves, CN5 has several nuclei in the brainstem. The three peripheral branches (remember their names?) all emanate from the caudal nucleus, which connects through the thalamus into the sensory system of the brain. The main job of the first division is to supply sensation to the eye and the orbit. It also supplies a large part of the dura, giving us our first hint at an association between ocular pain and head pain. Both the sympathetic and parasympathetic autonomic systems travel along parts of the trigeminal nerve as well. There appears to be ample opportunity for painful stimuli, both typical and atypical, to travel throughout to the head and neck.

Atypical ocular pain appears to be a processing problem. Allodynia is an abnormally increased central neuronal response to otherwise normal or typically nonpainful stimulation. Interestingly, in the context of DED, allodynia is often felt as a burning sensation. Makes sense, right? Temperature is a common stimulus that can provoke allodynia — also interesting, as there is a suggestion that aberrant firing of cold sensors in the cornea is associated with ocular pain. Continual firing of sensory nerves out of proportion to the stimulus is part of a unifying theory of head and neck pain along the trigeminal nerve.

Dr. Digre and her colleagues make a distinction between red-eye pain and white-eye pain. We are all familiar with red-eye pain; both aqueous deficient and evaporative DED are entities that cause red-eye pain. There are fascinating correlations between DED and migraine. Did you know that patients who suffer from migraine have been found to have decreased corneal nerve density? This has been seen in patients both with and without DED. Both patients with chronic migraine and patients with neurogenic eye pain often complain of photophobia. Is it possible that what we are seeing in the clinic is actually a form of migraine? I don’t know about you, but I will be exploring the use of migraine treatments for these patients.

To return to my original thought, I do not think that “neurogenic DED” actually exists, although “white-eye pain syndrome” does. While I was reading Dr. Digre’s Hoyt Lecture, I had an epiphany about how we might treat this vexing type of pain: Could the aberrant electrical “traffic” along the trigeminal nerve be akin to a cardiac arrhythmia? We know that there are several arrhythmias that can be converted back to normal sinus rhythm by overriding the aberrant electrical activity with an electrical “super-stimulus,” so-called cardioversion. Is this how neural stimulation works for pain? What if we could do the same thing with this aberrant electrical flow along the trigeminal nerve?


As it turns out we do, indeed, have the ability to do just this. TrueTear (Allergan) by its very nature produces a stimulus to afferent fibers of the first division of the trigeminal nerve inside the nose. This stimulus is certainly overwhelming in relation to the subclinical stimulus for the allodynia and responsible for white-eye pain. TrueTear does produce a sudden flow of a complete tear; this likely explains the symptomatic relief felt by typical DED patients. Most of us have prescribed TrueTear to our most challenging patients, including those with no classic signs of DED on the ocular surface. Many of them get better. Could this be why?

Neural stimulation with TrueTear independent of the production of tears may be the true mechanism of action of TrueTear. To my knowledge, this column is the first mention of a mechanism of action for directly stimulating the trigeminal nerve as a treatment for neurogenic pain. I encourage any of you who see these patients to consider TrueTear as an early intervention, as well as using traditional migraine treatments. This pain can be triggered initially by DED, but it is not itself a distinct form of DED. It is more appropriately categorized as a pain syndrome.

Given the obvious conflict of interest, I will leave it to others to decide if Dr. Digre’s descriptor (“white-eye pain”) becomes a name.

Disclosure: White reports he is a consultant to Allergan, Shire, Sun, Kala, Ocular Science, Rendia, TearLab, Eyevance and Omeros; is a speaker for Shire, Allergan, Omeros and Sun; and has an ownership interest in Ocular Science and Eyevance.